Recurrent Thyrotoxicosis After Subtotal Thyroidectomy

Author(s): Anthony J. Hedley, Iain P. Ross, J. Swanson Beck, David Donald, F. Albert-
Recht, W. Michie and James Crooks
Source: The British Medical Journal, Vol. 4, No. 5782 (Oct. 30, 1971), pp. 258-261
Published by: BMJ
Stable URL: http://www.jstor.org/stable/25416383
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 258 BRITISH MEDICAL JOURNAL 30 OCTOBER 1971

Recurrent Thyrotoxicosis after Subtotal Thyroidectomy

ANTHONY J. HEDLEY, IAIN P. ROSS, J. SWANSON BECK, DAVID DONALD,
F. ALBERT-RECHT, W. MICHIE, JAMES CROOKS

British Medical Journal, 1971, 4, 258-261 The long-acting thyroid stimulator (L.A.T.S.) is a humoral
factor present in the blood of certain patients with Graves's
Summary disease; it is generally accepted that this is an important factor
in the causation of hyperthyroidism in these patients rather
A study of patients with recurrent thyrotoxicosis after
subtotal thyroidectomy has shown that the operation than an epiphenomenon (Carneiro et al., 1966). In the present
has a profound effect on the natural history of Graves's study we have attempted to determine whether patients who
disease. It is followed by pronounced changes in the develop recurrent hyperthyroidism after subtotal thyroidectomy
immunological features of the disease, with a fall in the have persistent production of L.A.T.S. or whether they suffer
prevalence of serum thyroid autoantibodies, including from a basically different disease. The short-term and long-term
the long-acting thyroid stimulator. Thyroid suppression effects of subtotal thyroidectomy on the suppressibility of
returns to normal in 70% of patients. The treatment 132I uptake of the thyroid gland by triiodothyronine (T-3
suppression test) and the prevalance of thyroid autoantibodies
produces two populations of patients. In the larger in the serum have also been studied.
group there is a permanent remission of the disease
process. In the smaller group the disease process persists
and, consequently, recurrent hyperthyroidism may
develop. The mechanism of the change in the larger
group of patients probably has an immunological basis. Methods and Patients
Assay of L.A.T.S.?The L.A.T.S. activity in serum samples
was estimated by a modified McKenzie (1958) assay. The
Introduction "L.A.T.S. response" was considered positive when the mean
nine-hour mouse blood radioactivity was ^300% of the base
The prevalence of recurrent hyperthyroidism after subtotal
line, and greater than that at three hours; the justification for
thyroidectomy for Graves's disease varies considerably in adhering to this definition of the L.A.T.S. response has been
different centres, but it is invariably less than 30%, even when a
discussed previously (Hedley et al., 1970b). The mean saline
large remnant of thyroid tissue is left (Table I). There is
response in a large number of assays carried out over a three-year
period was 94-8 ? 3-6% at three hours (133 mice) and
table I?Prevalence of Recurrent Hyperthyroidism after Subtotal Thyroi 94-7 ? 3-8% at nine hours (160 mice).
dectomy for Graves's Disease Fractionation and Concentration of IgG from Patients' Sera.?
Prevalence of Recurrent The IgG fraction was separated with DEAE-Sephadex (A50)
Author Hyperthyroidism (%)
Jordan (1925) 6-7 in a batch method (Baumstark et al., 1964; Perper et al., 1967).
Thomson et al. (1930) 19-5
Clute and Veall (1932) 6-2 The mean initial serum sample volume was about 55 ml; in
Enzel(1932) .. 27-9 each case the eluate was concentrated by ultrafiltration under
Guette (1937) 6-5
Rasmussen (1937) 20-7 high-pressure nitrogen (Albert-Recht and Stewart, 1961) and
Cattell (1949) 2-4
Crile and McCullagh (1951) 150 reduced to a volume of 3 to 6 ml. The immunochemical purity
Hayles et al (1959) .. 17-9 of this fraction was assessed by immunoelectrophoresis (Schei
Riddell (1962) 3-3
Roy et al. (1967) 110 degger, 1955) against anti-whole-human serum and anti-human
Hedley et al. (1970a) 60
IgG antisera (Burroughs Wellcome; Hoechst Pharmaceuticals).
The concentration of IgG fractions was assayed by a radial
immunodiffusion technique (Fahey and McKelvey, 1965).
The incidence
evidence that radical resection results in a higher efficacy of theof
fractionation and concentration method was
postoperative hypothyroidism, but does not preventassessed in experiments
recurrence of on 10 potent L.A.T.S. sera and 3
L.A.T.S.-rich serum pools. The recovery of L.A.T.S. activity
hyperthyroidism in a small group of patients; furthermore,
was estimated from the slopes of the dose response lines in the
hyperthyroidism may recur despite multiple thyroidectomies
assay: findings
(McLarty et al, 1969; Hedley et al, 1970a). These
mean slope to of IgG concentrate n/ ? _,_
suggested that in some patients thyrotoxicosis is refractory
surgical treatment, and that in these patients the mean slope ofto
response whole serum -f-^-?:- - % recovery of L.A.T.S.
subtotal thyroidectomy is fundamentally differentThefrom
mean recovery
that ofof L.A.T.S. was 33-4% compared with
mean recovery of IgG of 34-6% in these samples.
most patients who remain euthyroid or become hypothyroid.
T-3 Suppression Tests.?Before subtotal thyroidectomy and
during antithyroid drug therapy the 20-minute uptake of 132I by
University of Aberdeen and Aberdeen Royal Infirmary
the thyroid
ANTHONY J. HEDLEY, m.b., Research Fellow, Department gland was measured before and after seven days'
of Thera
treatment
peutics and Pharmacology (Present appointment; Medical with 100 fig of T-3 daily (Thomas et al., 1960;
Registrar,
Therapeutics Unit, Maryfield Hospital, Dundee) Alexander et al., 1966); after thyroidectomy the four-hour
IAIN P. ROSS, PH.D., Research Assistant, Department of Therapeutics
uptake of 132I
and Pharmacology (Present appointment: Clinical Biochemist, by the thyroid gland was measured (Hobbs et al
Western
General Hospital, Edinburgh) 1963). In both tests T-3 suppression was regarded as significant
J. SWANSON BECK, m.d., f.r.c.p.(glasg., ed.), Senior Lecturer in
Pathology when the second uptake was less than 50% of the first uptake
DAVID DONALD, m.b., Lecturer in Pathology and less than 8% of the dose administered.
F. ALBERT-RECHT, m.b., Senior Lecturer in Chemical Pathology
W. MICHIE, m.b., f.r.c.s.ed., Consultant Surgeon Tests for Autoantibodies.?Antithyroid cytoplasmic antibody
JAMES CROOKS, m.d., f.r.c.p., Reader in Therapeutics (Present appoint was detected by an indirect immunofluoresence technique on
ment: Professor of Pharmacology and Therapeutics, University of cryostat sections of hyperplastic human thyroid gland, and the
Dundee)
results were recorded as negative, weak positive, and strong

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 BRITISH MEDICAL JOURNAL 30 OCTOBER 1971 259
positive, depending on the intensity of the fluorescence (Beck,
1971). AntithyroglobuHn antibody was detected by the forma
linized tanned red cell agglutination test (Fulthorpe et al., 1961);
sera with titres of 1/250 and 1/2,500 were considered as weak
positives and those > 1/2,500 as strong positives.
Anti-gastric-parietal-cell antibody was detected by an
indirect immunofluorescence test on cryostat sections of normal
human gastric mucosa (Beck, 1971).
PATIENTS WITH GRAVES'S DISEASE
All patients in this study had been treated for Graves's disease
with hyperthyroidism. The diagnosis was based on a clinical
examination (Crooks et al., 1959, 1960), measurement of serum
P.B.127I (AutoAnalyser Methodology N-56), and free thyroxine
index (Clark and Horn, 1965). In most cases scintiscanning,
measurement of uptake by the thyroid gland of 131I at four
hours and of P.B.131I at 48 hours, and suppression of the
four-hour uptake of 132I by T-3 was carried out. Particular care
was taken to exclude all patients who might have single or
multiple autonomous nodules.
Three groups of unselected patients were studied.
Group A, 53 Untreated Hyperthyroid Patients.?L.A.T.S. was
assayed in all patients before treatment; thyroidal suppressibility
was measured in 31 of them immediately before subtotal thyroid
ectomy and also during a prospective follow-up study between 6
and 17 months later.
Group B, 96 Untreated] Hyperthyroid Patients.?Thyroid auto
antibodies were measured in these patients who included the 53
patients in group A.
Group C, 141 Postthyroidectomy Patients.?These were taken
from a retrospective follow-up study. Thyroid autoantibodies were
measured in all patients; serum from 102 (6 recurrent hyperthyroid,
55 euthyroid, 41 hypothyroid) was assayed for L.A.T.S. and
thyroidal suppressibility was measured in 36 of the euthyroid group.
The age and sex distribution of the patients in groups B and C
were similar.
Two groups of selected patients were also studied.
Group D, 19 Patients with Recurrent Hyperthyroidism.?These
comprised 6 from the retrospective study (group C) and 13 addi
tional patients, in all of whom thyroid autoantibodies and L.A.T.S.
were estimated. Five of these patients had undergone a second
thyroidectomy for recurrent hyperthyroidism. Assays of serum and
concentrated IgG from 11 of these patients were compared with
similar observations on 11 of the patients in group E who were
matched exactly for age and time after operation.
Group E, 14 Euthyroid Postthyroidectomy Patients.?These were
from the retrospective study (group C); these patients acted as
controls in the IgG concentration experiments.
Results
ASSAY OF L.A.T.S.
Incidence of L.A.T.S. Responses in Patient Surveys.?A positive
L.A.T.S. response was found in 5 (9-4%) of the 53 untreated
hyperthyroid patients (group A) and in 2 (1-9%) of the 102
unselected postthyroidectomy patients (group Q? 1 out of 6
with recurrent thyrotoxicosis and 1 out of 96 without recurrence.
The prevalence of positive assays in the untreated hyperthyroid
patients was significantly higher than that in the whole group of
102 postthyroidectomy patients (P = 0-039). Three (15-7%) of
the 19 patients with recurrent hyperthyroidism (group D)
showed a positive L.A.T.S. response; the prevalence of this
abnormality did not differ statistically from that in untreated
hyperthyroid patients (P = 0-23) (Table II).
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table il?Prevalence of L.A.T.S. Responses in Patients with Graves's Disease
No. (%) of Patients in
Group Clinical State of Patients whom L.A.T.S. Response was
Positive Negative
A Untreated hyperthyroid .. 5 (9-4) 48 (90-6)
C Unselected postthyroidectomy .. 2 (1-9) 100 (98-1)
D Recurrent hyperthyroid .. 3 (15-7) 16 (84-3)
L.A.T.S. Responses in Fractionation and Concentration
Studies.?The whole serum of 11 patients from group D with
recurrent hyperthyroidism and 11 euthyroid controls from
group E, matched for age and time after operation, showed one
L.A.T.S. response in those with recurrence and none in the
euthyroid control group. When the concentrated IgG fractions
of these sera were assayed, 5 (45-5%) L.A.T.S. responses were
found in the recurrent hyperthyroid patients, including the
sample positive in unfractionated serum. None of the five
patients who had had two operations was positive with whole
serum, but two gave positive L.A.T.S. responses with IgG
fraction. The IgG fractions of the sera of the 11 euthyroid
patients were all negative in the L.A.T.S. assay (Fig. 1).
Serum IqC Serum IqC
HYPERTHYROID EUTHYROID
Postthyroidectomy thyroid status
fig. 1?L.A.T.S. responses in whole serum and IgG
fractions of 11 hyperthyroid and 11 euthyroid post
thyroidectomy patients matched for age and time after
operation.
T-3 SUPPRESSION TESTS
These tests were carried out during a prospective study of
group A hyperthyroid patients who were prepared for subtotal
thyroidectomy with conventional doses of antithyroid drugs.
Immediately before operation 7 (23-3%) out of 30 patents
showed significant suppression, whereas between 6 and 17
months after operation 22 (70*7%) out of 31 patients showed
significant suppression (x2 = 1203, P<0001). In this post
thyroidectomy group five patients were hypothyroid, and two
of them did not suppress. In 17 patients who were tested both
before and after operation five (29%) suppressed before opera
tion; after operation an additional seven patients suppressed,
giving a total of 12 (71%) (x2 = 4-2, P <005). In the retrospec
tive study (group C) of patients treated by subtotal thyroidect
omy between 2 and 21 years previously (mean 9-4 years),
30 (82-7%) out of 36 euthyroid patients tested showed complete
suppression. None of the 19 with recurrent hyperthyroidism
(group D) suppressed.
AUTOANTIBODIES
Antithyroid Cytoplasmic Antibodies.?The prevalence of positive
antithyroid cytoplasmic antibody tests was 48-4% in 136
euthyroid or hypothyroid postthyroidectomy patients from
260 BRITISH MEDICAL JOURNAL 30 OCTOBER 1971

table in?Prevalance of Autoantibodies in Patients with Graves's Disease

No. of Positive Tests (%)

Clinical State of Patients
No. of
Patients Antithyroid Cytoplasmic Antithyroglobulin Antibody Anti-gastric-parietal-cell
Antibody Antibody
Total Weak Strong Total Weak Strong Total Weak Strong
Untreated thyrotoxic 96 58 (60-4) 20 (20-8) 38 (39-8) 18 (18-8) 15 (15-6) 3 (3-1) 19 (19-8) 5 (5-2) 14 (14-6)
Postthyroidectomy, euthyroid and hypothyroid 136 66 (48-4) 31 (22-7) 35 (25-7) 18 (13-2) 17 (12-5) 1 (0-7) 25 (18-4) 8 (5-8) 17 (12-5)
Postthyroidectomy, recurrent hyperthyroidism .. 19 15 (78-9) 9 (47-3) 6 (31-6) 8 (42-1) 7 (36-8) 1 (5-3)

group C and 60-4% in the series of 96 untreated thyrotoxic Other studies have reported that between 60 and 100
patients with similar age distribution (x2 = 2-74, P>005); surgically treated patients revert to a normal suppr
however, the proportion of strongly positive tests was sig pattern (Werner, 1956; Eckert et al., 1960; Henneman
nificantly lower in the postthyroidectomy patients (x2 = 4-38, Bussemaker, 1969), but the time relationship of this chan
P<0-05). The incidence of positive antithyroid cytoplasmic the operation had not been defined. The numbers suppres
antibody tests was significantly higher in 19 patients (group D) after radioiodine therapy seem to be much smaller and do
with recurrent hyperthyroidism (78-9%) than in the post exceed 37% over similar follow-up periods (Werner,
thyroidectomy patients who were euthyroid or hypothyroid Eckert et al., 1960). Furthermore, there is no evidence
(x2 = 502, P<005) (Table III). conventional doses of 131I lead to a decrease in L.A.T.S. lev
Antithyroglobulin Antibody.?These tests were positive in (Pinchera et al., 1969), and even thyroid ablation doe
13-2% of the 136 postthyroidectomy patients and in 18-8% of always influence L.A.T.S. levels in patients with high t
the 96 untreated thyrotoxic patients (x2 = 009, P>005); the before treatment (Volpe et al., 1969; Hedley and Ross, 1
difference in the proportion of weakly and strongly positive The finding that 23% of patients suppressed before opera
tests did not reach significance at the 5% level. may be a consequence of antithyroid drug therapy. The ex
Anti-gastric-parietal-cell Antibody.?The prevalence of this to which antithyroid drugs may permanently suppres
antibody was similar in the untreated thyrotoxic (19-8%) and extrapituitary stimulus has not yet been clearly defined, bu
the postthyroidectomy (18-4%) patients (Table III). unlikely that they are the cause, in this study, of the pron
increase in the numbers of patients who reverted to a no
suppression pattern after operation. Spontaneous remissio
Discussion the disease process may be responsible for some case
reversion to normal suppression within the first year
It has been generally accepted that subtotal thyroidectomyoperation, but in view of the disparity between radioi
relieves the hyperthyroidism of Graves's disease by reducing and surgically treated patients it is unlikely to be an impo
the capacity of the gland to synthesize thyroxine. However, evenfactor.
after radical subtotal thyroidectomy an appreciable number of The study has shown that after operation there is a similar
patients develop recurrent hyperthyroidism; in a recent follow but less dramatic reduction in the levels of the two other
up study in North-east Scotland (Hedley et al., 1970a) the thyroid autoantibodies; however, subtotal thyroidectomy did
incidence of hypothyroidism was 35 %, but, nevertheless, over anot affect the incidence of anti-gastric-parietal-cell antibody.
21-year period 6% of the patients developed recurrent hyper This suggests that operative treatment has had a discriminating
thyroidism. Moreover, in a recent Glasgow series (McLartyeffect on thyroid autoimmunity in Graves's disease. It is
et al., 1969) comprising 90 patients with recurrent thyrotoxicosisnoteworthy that in the postthyroidectomy patients the anti
a second recurrence was found in nine who had been treatedthyroid cytoplasmic antibody is more frequent in patients with a
by two operations. In the present study a second recurrencerecurrence than in those who were euthyroid or hypothyroid.
was noted in five out of six patients who had had two operations These observations suggest that there is a parallelism between
for recurrent hyperthyroidism. These findings suggest that the L.A.T.S. and other thyroid autoantibodies.
patients who developed recurrent hyperthyroidism may have
responded to operation in a fundamentally different way from
the rest. IMMUNOLOGICAL CHANGES
In interpreting the results of our investigations we have
assumed that the thyroid function of patients with a normal The immediate effect of subtotal thyroidectomy is a reduction
T-3 suppression test is controlled by pituitary thyrotropin andin the capacity of the gland to synthesize thyroid hormone,
conversely that failure to suppress indicates the presence of an but there is evidence that it also influences the basic process in
extrapituitary stimulator, probably L.A.T.S. Graves's disease. The reversion to normal thyroidal suppression
The incidence of L.A.T.S. responses in serum of patientsand the apparent disappearance of L.A.T.S. in most patients
with recurrent hyperthyroidism after subtotal thyroidectomyindicate a remarkable change in the autoimmune status, not
is more than twice that found in an unselected group of patientsseen after radioiodine or antithyroid drug treatment. It has been
with untreated hyperthyroidism. This finding supports theshown previously that small amounts of thyroglobulin are
concept that L.A.T.S. is an important aetiological factor in the released into the thyroid lymph under physiological conditions,
pathogenesis of recurrent hyperthyroidism, though it does not and that this is greatly increased by manipulation of, or surgical
indicate whether this is persistent or renewed production of trauma to, the gland (Lerman, 1940; Hjort, 1961; Daniel et al.,
L.A.T.S. after subtotal thyroidectomy. However, this study1967). It is therefore probable that, during and immediately
has also shown that subtotal thyroidectomy leads to normalafter subtotal thyroidectomy, there is a sudden release of
thyroidal suppressibility in over 70% of patients in the early thyroid epithelial cell components and colloid into the blood
postoperative period, which is more than twice the number whoand lymphatic circulations. It is possible that the sudden
suppressed during the preparatory antithyroid drug therapy. Amassive release of antigens may have immunological conse
retrospective study confirmed that the failure to suppressquences; these will be determined by the relative quantities of
persists in 20% of patients, up to 20 years after operation in different antigens released, their relative immunogenicity, and
some cases. the reaction of the immunological system towards them.

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 BRITISH MEDICAL JOURNAL 30 OCTOBER 1971 261
We consider that it is improbable that these patients have
changed production from L.A.T.S. which is known to be an
IgG, to a "blocking" antibody of a different Ig class but of the
same specificity, loosely analogous to "desensitization"treatment
for reaginic disease. This is unlikely, since production of some
IgG antibody would be expected to continue, though it must be
admitted that this possibility cannot be excluded because the
methods for the detection of L.A.T.S. are insensitive. At the
present time it is simpler to presume that, after subtotal thyroi
dectomy, these patients cease production of antibody with the
physiological action of L.A.T.S., and in this respect most
patients seem to revert from autoimmunity to physiological
immunity. This apparent permanent remission amounts to a
therapy-induced "cure" of an autoimmune reaction that is
without precedent in man. It could be explained by a re
acquisition of normal immunological tolerance or by develop
ment of secondarily induced immunological paralysis?though
the underlying mechanism for these two possibilities may be
different, the clinical effects would be similar.
TWO GROUPS
After subtotal thyroidectomy the patients seem to fall into two
groups (Fig. 2) : a larger group who reacquire normal thyroidal
suppressibility and a smaller group who remain non-suppress
$8? ??s?^ '?V
(70ofe)
Thyrotropin Thyrotropin + LAIS.
Remnant size Remnant size
Thyroid it is Thyroiditis
Remnant blood supply Remnant blood supply
Dietary iodine Dietary iodine
fig. 2?Diagrammatic representation of factors which may determine the
effect of subtotal thyroidectomy in patients with thyrotoxic Graves's disease.
ible. The postoperative thyroid status of patients in each group
will be determined by a number of variable factors, such as
stimulation of the gland by pituitary thyrotropin (Hedley et al.,
1971) and L.A.T.S., the size of the remnant, the presence and
extent of thyroiditis, the blood supply of the remnant, and
dietary iodine levels. Recurrent hyperthyroidism will occur
only in the smaller unsuppressed group, which we have shown
to be limited to a maximum of 20 to 30%. Recurrences are
probably prevented in most of the patients at risk by radical
resection of tissue and/or progressive damage by thyroiditis.
Thus attempts to reduce the incidence of postoperative hypo
thyroidism by increasing the size of the remnant left at operation
will probably result in an increased incidence of recurrent
hyperthyroidism in the unsuppressed group.
At present it is not possible to predict before operation
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whether a patient will suppress or fail to suppress after subtotal
thyroidectomy. When this can be done, and if subtotal thyroi
dectomy remains a standard method of treating thyrotoxicosis,
it will become possible to rationalize therapy; the remnants
would be larger in the postoperative suppressors to reduce the
incidence of hypothyroidism and smaller in the non-suppressors,
a greater proportion of whom would develop recurrent thyro
toxicosis if a larger remnant was left.
We are grateful to Dr. M. I. Chesters and Mr. J. A. Hetherington
for help and advice in the isotope studies, and to Dr. G. Hems for
help with the statistics.
One of us (I.P.R.) was supported by a grant from the Scottish
Hospitals Endowment Research Trust and the study was also
supported in part by the Medical Research Council.
Requests for reprints should be addressed to Dr. A. J. Hedley,
Therapeutics Unit, Maryfield Hospital, Dundee.
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